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Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile.

Authors
Type
Published Article
Journal
Antimicrobial Agents and Chemotherapy
1098-6596
Publisher
American Society for Microbiology
Publication Date
Volume
58
Issue
4
Pages
2387–2392
Identifiers
DOI: 10.1128/AAC.00021-14
PMID: 24514098
Source
Medline
License
Unknown

Abstract

Clostridium difficile is the causative agent of C. difficile-associated diarrhea (CDAD), with increased risk in elderly populations. Kibdelomycin, a novel natural-product inhibitor of type II topoisomerase enzymes, was evaluated for activity against C. difficile and gastrointestinal anaerobic organisms. Toxigenic C. difficile isolates (n=168) from U.S. hospitals and anaerobic Gram-positive and Gram-negative organisms (n=598) from Chicago-area hospitals were tested. Kibdelomycin showed potent activity against toxigenic C. difficile (MIC90=0.25 μg/ml) and most Gram-positive aerobic organisms but had little activity against Bacteroides species (MIC50>32 μg/ml; n=270). Potent anti-C. difficile activity was also observed in the hamster model of C. difficile colitis. Dosing at 1.6 mg/kg (twice-daily oral dose) resulted in protection from a lethal infection and a 2-log reduction in C. difficile cecal counts. A 6.25-mg/kg twice-daily oral dose completely eliminated detectable C. difficile counts in cecal contents. A single 6.25-mg/kg oral dose showed that cecal contents were exposed to the drug at >2 μM (eightfold higher than the MIC), with no significant plasma exposure. These findings support further exploration of kibdelomycin for development of an anti-C. difficile agent.

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